Derivatives of indan-1,3-dione and indan-1,2,3-trione, methods of preparing them and therapeutic use thereof

ABSTRACT

Therapeutic compounds having the formula: ##STR1## in which R 2  and R 3  independently denote H, C 1  -C 4  alkoxy or OH and (A, B)=(oxygen, oxygen) in which case one out of R and R 1  denotes OH, halogen, secondary amino or tertiary amine and the other denotes NHNHCONHR 4  or R and R 1  together denote ═N--NH--CX--NHR 5 , ═N--NH--CX--N(phenyl) 2 , ═N--NH--CX--NH--NH--R 5 , ═N--NH--C(SCH 3 )═N--R 6  or ═N--N═C(SCH 3 )--NH--R 6  ; or (A, B)=(N--OH, oxygen) in which case R and R 1  together form ═N--NH--CX--NHR 5  or ═N--NH--CX--N(phenyl) 2  ; or (A, B)=(N--NH--CX--NHR 5 , oxygen) in which case R and R 1  together form ═N--NH--CX--NHR 5  ; or (A, B)=(N--OH, N--OH) in which case R and R 1  together form ═N--NH--CX--NHR 5  or ═N--NH--CX--N(phenyl) 2 .

This application is a 371 of PCT/FR93/00328, filed Apr. 1, 1993.

The invention relates to novel derivatives of indan-1,2-dione andindan-1,2,3-trione, methods of preparation thereof and use thereof intherapy.

More specifically, these derivatives have the formula: ##STR2## in whichR₂ and R₃ independently denote H, C₁ -C₄ alkoxy or OH, and the pair (A,B) denotes either:

(oxygen, oxygen), in which case one out of R and R₁ denotes OH, halogen,(C₁ -C₄ alkyl) NH, N-morpholino(C₁ -C₄ alkyl) NH,1-(pyridyl)-4-piperazino or 1-(phenyl)-4-piperazino in which the phenylring is optionally substituted by a halogen, and the other denotes anNHNHCONHR₄ group where R₄ =phenyl or phenyl substituted by OH or C₁ -C₄alkyl and

R and R₁ may also together form a group, i.e.:

═N--NH--CX--NHR₅ where X represents oxygen or sulphur and R₅ =H,pyridyl, phenyl or phenyl substituted by one, two or three groups chosenfrom among OH, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, methylenedioxy, acetoxy or hydroxyethyl, or

═NNHCXN (phenyl)₂, where X denotes oxygen or sulphur or

═N--NH--CX--NH--NH--R₅ where X and R₅ have the same meanings ashereinbefore, or

═N--NH--C(SCH₃)═NR₆ or ═N--N═C(SCH₃)--NHR₆ where R₆ denotes phenyl orphenyl substituted by one, two or three groups chosen from among OH,CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen, methylene dioxy, acetoxy orhydroxyethyl or

(N--OH, oxygen) in which case R and R₁ together form an ═NNHCXNHR₅ or═NNHCXN (phenyl)₂ group, where X and R₅ have the same meanings ashereinbefore, or

(NNHCXNHR₅, oxygen), where X and R₅ have the same meanings ashereinbefore, in which case R and R₁ together form an ═NNHCXNHR₅ groupor

(N--OH, N--OH), in which case R and R₁ together form an ═NNHCXNHR₅ groupwhere X and R₅ have the same meanings as hereinbefore, or an═N--NH--CX--N (phenyl)₂.

Formula (I) hereinbefore includes:

(i) compounds having the formula: ##STR3## where R, R₁, R₂ and R₃ havethe same meanings as in formula (I) when the pair (A, B) therein denotes(oxygen, oxygen),

(ii) compounds having the formula: ##STR4## where R, R₁, R₂ and R₃ havethe same meanings as in formula (I), when the pair (A, B) thereindenotes (═N--OH, oxygen),

(iii) compounds having the formula: ##STR5## where R₂, R₃, X and R₅ havethe same meanings as in formula (I), and

(iv) compounds having the formula: ##STR6## where R₂, R₃, X and R₅ havethe same meanings as in formula (I).

Formula (I) hereinbefore includes:

(a) compounds having the formula: ##STR7## (b) compounds having theformula: ##STR8## (c) compounds having the formula: ##STR9## where oneout of R and R₁ denotes NHNHCONHR₄ and the other denotes (C₁ -C₄ alkyl)NH, N-morpholino (C₁ -C₄ alkyl) NH, 1-(pyridyl)-4-piperazino or1-(phenyl)-4-piperazino in which the phenyl ring is optionallysubstituted by a halogen,

(d) compounds having the formula: ##STR10## (e) compounds having theformula: ##STR11## (f) compounds having the formula: ##STR12## (g)compounds having the formula: ##STR13## (h) compounds having theformula: ##STR14## (i) compounds having the formula: ##STR15## (j)compounds having the formula: ##STR16## (k) compounds having theformula: ##STR17## (l) compounds having the formula: ##STR18## and (m)compounds having the formula: ##STR19## in which the symbols R₂, R₃, R₄,R₅ and X have the same meanings as in formula (I).

In formulae (I') to (I"") and (Ia) to (Im) hereinbefore, R₂ is interalia in position 5 and R₃ in position 6.

Also, in formulae (I') to (I"") and (Ia) to (Im), the pair (R₂, R₃) mayinter alia be (H, H), (5--OCH₃,H), (5--OH, H) or (5--OCH₃, 6--OCH₃).

The invention also covers salts of the salt-forming compounds amongthose described hereinbefore. These salts comprise addition salts ofmineral acids such as hydrochloric, hydrobromic, sulphuric or phosphoricacid, and addition salts of organic acids such as acetic, propionic,oxalic or citric acid.

The invention also covers all possible stereoisomers of formula (I)derivatives and mixtures of such stereoisomers, as well as themetabolites of these derivatives.

The invention also covers methods of preparing formula (I) derivatives.These methods are described in diagrams 1 to 6 hereinafter, in which thesymbols R to R₆ and X, unless stated otherwise, have the same meaningsas in formula (I). ##STR20##

In the diagrams hereinbefore, 1 to 9 denote the methods used and havethe following meanings:

1 Condensation in a solvent such as ethanol, hot and preferablyrefluxed.

2 Reaction with a halogenating agent, inter alia a chlorinating agent,preferably thionyl chloride, in a solvent such as THF, hot andpreferably refluxed.

3 Condensation with a primary amine [(C₁ -C₄ alkyl)NH₂ orN-morpholino(C₁ -C₄ alkyl) NH₂ ] or a secondary amine[1-pyridyl-4-piperazine or 1-(phenyl)-4-piperazine in which the phenylring is optionally substituted by a halogen atom] in a solvent such asdiethyl ether, in the presence of a base such as triethylamine.

4 Condensation of the semicarbazide or thiosemicarbazide inhydrochloride form in a solvent such as an ethanol-water mixture, hotand preferably refluxed, or

Condensation of the semicarbazide or thiosemicarbazide in a solvent suchas ethanol, preferably at ambient temperature.

5 Condensation in a solvent, inter alia an aqueous solution of ethanol,preferably at ambient temperature, followed by treatment of the reactionproduct with HCl in ethanol.

6 Condensation in a solvent, inter alia an aqueous solution of ethanol,hot. Note that the (Ig) formula compounds may also exist in thetautomeric form (Ih).

7 Condensation with hydroxylamine hydrochloride in the presence ofsodium acetate and in a solvent such as aqueous ethanol, hot andpreferably refluxed.

8 The same reaction conditions as in 4 but using two equivalents ofsemicarbazide or thiosemicarbazide.

9 Hot condensation preferably with reflux in a solvent such as aqueousethanol, in the presence of sodium acetate.

The following preparations are given by way of example to illustrate theinvention.

A. Preparation of the Raw Materials

EXAMPLE A 5-hydroxyindan-1,3-dione

4 ml of 10N sulphuric acid were added to a suspension of 0.01 mol of5-acetoxy-2-carbethoxy-3-hydroxy-1-indanone in 80 ml water. The reactionmixture was refluxed for 15 minutes. The insoluble substance wasfiltered when hot and the yellow precipitate formed after cooling wasdried on vacuo pump, washed in ice water and dried.

Yield: 85%; M.P.: 208° C.; IR: υ OH=3250 cm⁻¹, υ CO=1730 and 1680 cm⁻¹.

EXAMPLE B 2-bromo-5-hydroxyindan-1,3-dione

0.02 mol bromine was added dropwise to a solution of 0.02 mol of5-hydroxyindan-1,3-dione in 60 ml chloroform. The reaction mixture wasagitated at 50° C. for 30 minutes and the precipitate obtained afterevaporation of the solvent was recrystallised.

Yield: 60%; M.P.: 194° C.; IR: υ OH=3380 cm⁻¹, υ CO=1740 and 1710 cm⁻¹.

Recrystallisation solvent: a mixture (V/V) of ethyl ether and petroleumether.

EXAMPLE C 5-hydroxyindan-1,2,3-trione, monohydrate

A solution of 0.01 mol of 2-bromo-5-hydroxyindan-1,3-dione in 10 mldimethyl sulphoxide was heated to 80° C. for 30 minutes. 50 ml of a 1Nhydrochloric acid solution was added, after which heating was continuedfor 30 minutes. The oily suspension obtained after cooling was extractedwith ethyl ether. The organic phase was washed in water and dried overmagnesium sulphate.

The yellow precipitate obtained after evaporation of the solvent wasrecrystallised from water.

Yield: 45%; M.P.:>265° C.; IR: υ OH=3340 cm⁻¹, υ CO=1750 and 1710 cm⁻¹.

EXAMPLE D 5,6-dimethoxyindan-1,2,3-trione, monohydrate

0.06 mol of selenium oxide in solution in 2.5 ml water was added to asolution of 0.03 mol of 5,6-dimethoxy-1-indanone in 100 ml dioxan. Thereaction mixture was refluxed for 7 hours and the residue obtained afterevaporation of the solvent was dissolved in ethyl acetate. The organicphase was washed several times in water, dried over magnesium sulphateand decolorized.

The precipitate obtained after evaporation of the solvent wasrecrystallised from ethyl ether.

Yield: 50%; M.P.: 170° C.; IR: υ CO=1730 and 1700 cm⁻¹.

EXAMPLE E 6-hydroxy-5-methoxyindan-1,2,3-trione, monohydrate

0.06 mol of selenium oxide in solution in 2.5 ml water was added to asolution of 0.03 mol of 6-hydroxy-5-methoxy-1-indanone in 100 ml dioxan.The reaction mixture was refluxed for 7 hours and the residue obtainedafter evaporation of the solvent was dissolved in ethyl acetate. Theorganic phase was washed several times in water, dried over magnesiumsulphate and decolorized.

The precipitate obtained after evaporation of the solvent wasrecrystallised from water.

Yield: 50%; M.P.>265° C.; IR: υ CO=1740 and 1700 cm⁻¹.

EXAMPLE F 2-oximino-5-hydroxyindan-1,3-dione

0.02 mol of sodium nitrite in solution in 8 ml water was added dropwise,keeping the temperature at 5° C., to a suspension of 0.01 mol of5-hydroxyindan-1,3-dione in 6 ml of 2N sulphuric acid solution. Thereaction mixture was agitated at 5° C. for 4 hours. The insolublesubstance was dried on suction pump, washed in water, dried andrecrystallised from acetone.

Yield: 65%; M.P.: 220° C.; IR: υ OH=3400 and 3260 cm⁻¹, υ CO=1730 and1690 cm⁻¹.

Reference hereinafter is made to ninhydrin. Note that this substance isalso known under the name indan-1,2,3-trione monohydrate or the name of2,2-dihydroxy-1,3-dioxo-2H-indene. These three names are used withoutdistinction hereinbefore and hereinafter.

B. Preparation of formula (Ia) and (Ib) compounds

METHOD 1

0.01 mol of H₂ N--NH--CO--NH--R₅ in solution in 20 ml ethanol was addedto a solution of 0.01 mol of optionally substituted ninhydrin in 20 mlethanol. The reaction mixture was heated to 60° C. for 5 to 15 minutesand the resulting white precipitate was dried on suction pump, washed inethyl ether and dried.

METHOD 2

3.5 ml (0.04 mol) of thionyl chloride was added dropwise to a solutionof 0.02 mol of the compound obtained by method 1 in 20 mltetrahydrofuran. The reaction mixture was refluxed for an hour. Theresidual oil obtained after evaporating the excess thionyl chloride andtetrahydrofuran crystallised after washing in petroleum ether.

EXAMPLE 1 2-hydroxy-2-[4(2-hydroxyphenyl)-semicarbazido]indan-1,3-dioneMETHOD 1

Raw materials: ninhydrin and 4-(hydroxyphenyl)-semicarbazidehydrochloride. Yield: 90%; M.P. 190° C.; IR: υ OH=3400 cm⁻¹, υ NH=3210cm⁻¹, υ CO=1760, 1720 and 1640 cm⁻¹.

C. Preparation of formula (Ic) compounds

METHOD 3

1 ml of triethylamine was added to a solution of 0.007 mol of formula(Ib) compound in 60 ml ethyl ether. The mixture was agitated for 5minutes, then 0.007 mol of amine was added. The reaction mixture wasagitated at ambient temperature for 2 hours. The resulting precipitatewas dried on suction pump, repeatedly washed in water, dried andrecrystallised.

D. Preparation of formula (Id) and (Ie) compounds

METHOD 4

0.01 mol of the corresponding semicarbazide (or thiosemicarbazide)hydrochloride in solution in 10 ml water was added to a solution of 0.01mol of optionally substituted ninhydrin in 50 ml ethanol.

The reaction mixture was refluxed for 1 hour (or 30 minutes in examples11 to 14). The precipitate formed was dried on suction pump when hot (orcold in examples 12 to 15), dried and recrystallised.

In the case where the precipitate was a mixture of mono anddisubstituted compounds, separation was brought about by fractionalrecrystallisation.

EXAMPLE 2 2-semicarbazono-indan-1,3-dione

Raw materials: ninhydrin, semicarbazide hydrochloride.

Yield: 70%; M.P. 255° C.; IR: υ NH₂ and NH=3450, 3350 and 3220 cm⁻¹, υCO=1720 and 1680 cm⁻¹.

Recrystallisation solvent: acetonitrile.

EXAMPLE 3 2-(4-phenyl semicarbazono)-indan-1,3-dione

Raw materials: ninhydrin, 4-phenyl semicarbazide hydrochloride.

Yield: 40%; M.P. 220° C.; IR: υ NH=3350 and 3250 cm⁻¹, υ CO=1730, 1715and 1680 cm⁻¹.

Recrystallisation solvent: ethyl acetate

EXAMPLE 4 2-[4-(2-hydroxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-hydroxyphenyl)-semicarbazidehydrochloride

Yield: 50%; M.P. 260° C.; IR: υ OH=3460 cm⁻¹, υ NH=3370 and 3250 cm⁻¹, υCO=1735 and 1680 cm⁻¹.

Recrystallisation solvent: ethanol

EXAMPLE 5 2-(4-phenyl thiosemicarbazono)-indan-1,3-dione

Raw materials: ninhydrin, 4-phenyl thiosemicarbazide hydrochloride

Yield: 45%; M.P. 222° C.; IR: υ NH=3360 and 3240 cm⁻¹, υ CO=1730 and1680 cm⁻¹.

Recrystallisation solvent: ethanol.

EXAMPLE 6 2-[4-(2-methoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-methoxyphenyl)-semicarbazidehydrochloride.

Yield: 80%; M.P. 235° C.; IR: υ NH=3360 and 3240 cm⁻¹, υ CO=1730 and1690 cm⁻¹.

Recrystallisation solvent: methanol

EXAMPLE 7 2-[4-(3-methoxyphenyl)-semicarbazono]indan-1,3-dionemonohydrate

Raw materials: ninhydrin, 4-(3-methoxyphenyl)-semicarbazidehydrochloride

Yield: 70%; M.P. 195° C.; IR: υ OH=3600 and 3500 cm⁻¹, υ NH=3260 cm⁻¹, υCO=1725 and 1680 cm⁻¹.

Recrystallisation solvent: ethanol

EXAMPLE 8 2-[4-(4-methoxyphenyl)-semicarbazono]indan-1,3- dione

Raw materials: ninhydrin, 4-(4-methoxyphenyl)-semicarbazidehydrochloride

Yield: 80%, M.P. 218° C.; IR: υ NH=3280 and 3220 cm⁻¹, υ CO=1720 and1665 cm-1.

Recrystallisation solvent: isopropanol

EXAMPLE 9 2-[4-(2,5,-dimethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2,5-dimethoxyphenyl)-semicarbazidehydrochloride

Yield: 75%; M.P. 222° C.; IR: υ NH=3340 and 3200 cm⁻¹ ; υ CO=1730 and1690 cm⁻¹

Recrystallisation solvent: isopropanol

EXAMPLE 10 2-[4-(3,5-dimethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3,5-dimethoxyphenyl)-semicarbazidehydrochloride

Yield: 80%; M.P. 234° C.; IR: υ NH=3380 and 3230 cm⁻¹ ; υ CO=1730 and1690 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 11 2-[4-(3,4-dimethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3,4-dimethoxyphenyl)-semicarbazidehydrochloride

Yield: 70%; M.P. 210° C.; IR: υ NH=3400 and 3260 cm⁻¹ ; υ CO=1720 and1670 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 12 2-[4-(2-chloro-5-methoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-chloro-5-methoxyphenyl)-semicarbazidehydrochloride

Yield: 80%; M.P. 228° C.; IR: υ NH=3330 and 3260 cm⁻¹ ; υ CO=1730 and1680 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 13 2-(4,4-diphenylsemicarbazono)-indan-1,3-dione

Raw materials: ninhydrin, 4,4-diphenyl semicarbazide hydrochloride

Yield: 45%; M.P. 256° C.; IR: υ NH=3200 cm⁻¹, υ CO=1720, 1700 and 1670cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 14 2-[4-(2-methylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-methylphenyl)-semicarbazide hydrochloride

Yield: 60%; M.P. 192° C.; IR: υ NH=3340 and 3210 cm⁻¹ ; υ CO=1720 and1675 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 15 2-[4-(3-methylphenyl)-semicarbazon]indan-1,3-dione,monohydrate

Raw materials: ninhydrin, 4-(3-methylphenyl)-semicarbazide hydrochloride

Yield: 95%; M.P. 128° C.; IR: υ NH=3260 and 3240 cm⁻¹ ; υ CO=1720 and1670 cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 16 2-[4-(4-methylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-methylphenyl)-semicarbazide hydrochloride

Yield: 74%; M.P. 208° C.; IR: υ NH=3380 and 3200 cm⁻¹ ; υ CO=1720 and1670 cm⁻¹

Recrystallisation solvent: ethyl ether

EXAMPLE 17 2-[4-(4-propylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-propylphenyl)-semicarbazide hydrochloride

Yield: 74%; M.P. 166° C.; IR: υ NH=3215 cm⁻¹ ; υ CO=1710 and 1680 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 18 2-[4-(4-tert-butylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-tert-butylphenyl)-semicarbazidehydrochloride

Yield: 40%; M.P. 258° C.; IR: υ NH=3360 and 3200 cm⁻¹ ; υ CO=1710 and1670 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 19 2-[4-(2-chlorophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-chlorophenyl)-semicarbazide hydrochloride

Yield: 75%; M.P. 208° C.; IR: υ NH=3330 and 3220 cm⁻¹ ; υ CO=1710 and1670 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 20 2-[4-(2-chloro-6-methylphenyl )-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-chloro-6-methylphenyl)-semicarbazidehydrochloride

Yield: 75%; M.P. 228° C.; IR: υ NH=3320 and 3200 cm⁻¹ ; υ CO=1710 and1670 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 21 2-[4-(4-chlorophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-chlorophenyl)-semicarbazide hydrochloride

Yield: 75%; M.P. 234° C.; IR: υ NH=3300 and 3280 cm⁻¹ ; υ CO=1730 and1680 cm⁻¹

Recrystallisation solvent: isopropanol

EXAMPLE 22 2-[4-(2,5-diethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2,5-diethoxyphenyl)-semicarbazidehydrochloride

Yield: 40%; M.P. 226° C.; IR: υ NH=3340 cm⁻¹ ; υ CO=1720 and 1675 cm⁻¹

Recrystallisation solvent: isopropanol

EXAMPLE 23 2-[4-ethylthiosemicarbazono)-indan-1,3-dione

Raw materials: ninhydrin, 4-ethyl thiosemicarbazide hydrochloride

Yield: 30%; M.P. 212° C.; IR: υ NH=3340 and 3240 cm⁻¹ ; υ CO=1720 and1670 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 24 2-(4-methylthiosemicarbazonol-indan-1,3-dione

Raw materials: ninhydrin, 4-methyl thiosemicarbazide hydrochloride

Yield: 70%; M.P. 234° C.; IR: υ NH=3200 cm⁻¹ ; υ CO=1710 and 1670 cm⁻¹

Recrystallisation solvent: a (V/V) mixture of methanol and ethyl acetate

EXAMPLE 25 2-[4-(4-ethylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-ethylphenyl)-semicarbazide hydrochloride

Yield: 60%; M.P. 180° C.; IR: υ NH=3330 and 3220 cm⁻¹ ; υ CO=1715 and1670 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 26 2-[4-(3-ethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3-ethoxyphenyl)-semicarbazide hydrochloride

Yield: 85%; M.P. 164° C.; IR: υ NH=3240 cm⁻¹ ; υ CO=1730 and 1680 cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 27 2-[4-(4-ethoxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-ethoxyphenyl)-semicarbazide hydrochloride

Yield: 70%; M.P. 200° C.; IR: υ NH=3300 and 3210 cm⁻¹ ; υ CO=1720 and1670 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 28 2-[4-(2,4-dichlorophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2,4-dichlorophenyl)-semicarbazidehydrochloride

Yield: 35%; M.P. 226° C.; IR: υ NH=3315 and 3210 cm⁻¹ ; υ CO=1710 and1670 cm⁻¹

Recrystallisation solvent: isopropanol

EXAMPLE 29 2-[4-(3,4-methylenedioxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3,4-methylenedioxyphenyl)-semicarbazidehydrochloride

Yield: 70%; M.P. 228° C.; IR: υ NH=3250 cm⁻¹ ; υ CO=1715 and 1670 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 30 2-[4-(2-fluorophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-fluorophenyl)-semicarbazide hydrochloride

Yield: 80%; M.P. 195° C.; IR: υ NH=3310 and 3210 cm⁻¹ ; υ CO=1720, 1700and 1665 cm⁻¹

Recrystallisation solvent: methanol/ethyl acetate (V/V)

EXAMPLE 31 2-[4-(3-fluorophenyl)-semicarbazono]indan=1,3-dione

Raw materials: ninhydrin, 4-(3-fluorophenyl)-semicarbazide hydrochloride

Yield: 90%; M.P. 222° C.; IR: υ NH=3360 and 3230 cm⁻¹ ; υ CO=1740 and1695 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 32 2-[4-(4-fluorophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-fluorophenyl)-semicarbazide hydrochloride

Yield: 80%; M.P. 230° C.; IR: υ NH=3320 and 3200 cm⁻¹ ; υ CO=1710 and1660 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 33 2-[4-(2-bromophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-bromophenyl)-semicarbazide hydrochloride

Yield: 80%; M.P. 235° C.; IR: υ NH=3320 and 3220 cm⁻¹ ; υ CO=1715 and1680 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 34 2-[4-(4-bromophenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(4-bromophenyl)-semicarbazide hydrochloride

Yield: 80%; M.P. 236° C.; IR: υ NH=3230 cm⁻¹ ; υ CO=1750, 1730 and 1690cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 35 2-[4-(2-hydroxyethyl)-semicarbazono]-1,3-dione

Raw materials: ninhydrin, 4-(2-hydroxyethyl)-semicarbazide hydrochloride

Yield: 70%; M.P. 247° C.; IR: υ OH/NH=3360, 3240 and 3220 cm⁻¹ ; υCO=1710 and 1680 cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 36 2-[4-(2-acetoxyphenyl)-semicarbazono]indan-1,3-dione

Two drops of concentrated sulphuric acid were added to a solution of 1 g(0.003 mol) of 2-[4-(2-hydroxyphenyl)-semicarbazono]indan-1,3-dione(example 4) in 10 ml acetic anhydride.

The reaction mixture was agitated at ambient temperature for 10 minutes,then poured into ice water. The resulting yellow precipitate was driedon suction pump, repeatedly washed with water, dried and recrystallisedfrom acetonitrile.

Yield: 45%; M.P. 242° C.; IR: υ NH=3320 and 3180 cm⁻¹ ; υ CO=1740, 1715and 1675 cm⁻¹

EXAMPLE 37 5-methoxy-2-(4-phenylsemicarbazono)-indan-1,3-dione

Raw materials: 5-methoxyindan-1,2,3-trione, monohydrate, 4-phenylsemicarbazide hydrochloride

Yield: 61%; M.P. 230° C.; IR: υ NH=3250 cm⁻¹ ; υ CO=1720 and 1680 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 38 5-methoxy-2-(4-phenylthiosemicarbazono)-indan-1,3-dione

Raw materials: 5-methoxyindan-1,2,3-trione, monohydrate, 4-phenylthiosemicarbazide hydrochloride

Yield: 48%; M.P. 149° C.; IR: υ NH=3260 cm⁻¹, υ CO=1720 and 1680 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 39 5-methoxy-2-semicarbazono-indan-1,3-dione

Raw materials: 5-methoxyindan-1,2,3-trione, monohydrate, semicarbazidehydrochloride

Yield: 86%; M.P.>265° C.; IR: υ NH=3320 and 3220 cm⁻¹, υ CO=1720 and1680 cm⁻¹

Recrystallisation solvent: mixture (V/V) of ethanol and ethyl acetate

EXAMPLE 405-methoxy-2-[4-(2-hydroxyphenyl)-semicarbazono]indan-1,3-dione

Raw materials: 5-methoxyindan-1,2,3-trione, monohydrate,4-(2-hydroxyphenyl)-semicarbazide hydrochloride; reflux for 5 hours

Yield: 60%; M.P. 262° C.; IR: υ OH=3400 cm⁻¹, υ NH=3300 cm⁻¹, υ CO=1750,1700 and 1620 cm⁻¹

Precipitate washed in ether.

EXAMPLE 41 5-methoxy-2-thiosemicarbazono-indan-1,3-dione

Raw materials: 5-methoxyindan-1,2,3-trione, monohydrate,thiosemicarbazide hydrochloride

Yield: 43%; M.P.>265° C.; IR: υ NH=3220 and 3120 cm⁻¹, υ CO=1710 and1655 cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 42 5-hydroxy-2-(4-phenylsemicarbazono),indan-1,3-dione

Raw materials: 5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenylsemicarbazide hydrochloride; reflux for 4 hours

Yield: 70%; M.P. 265° C.; IR: υ OH=3400 cm⁻¹, υ NH=3240 and 3220 cm⁻¹, υCO=1680 cm⁻¹

Recrystallisation solvent: acetonitrile

EXAMPLE 43 5-hydroxy-2-semicarbazono-indan-1,3-dione

Raw materials: 5-hydroxyindan-1,2,3-trione, monohydrate, semicarbazidehydrochloride, reflux for 4 hours.

Yield: 50%; M.P.>265° C.; IR: υ OH/NH₂ =3420 cm⁻¹, υ CO=1720 and 1660cm⁻¹

Recrystallisation solvent: ethanol

EXAMPLE 44 5-hydroxy-2-(4-phenylthiosemicarbazono)-indan-1,3-dione

Raw materials: 5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenylthiosemicarbazide hydrochloride, reflux for 2 hours.

Yield: 45%; M.P.>265° C.; IR: υ OH=3400 cm⁻¹, υ NH=3300 and 3120 cm⁻¹, υCO=1710 and 1675 cm⁻¹

Recrystallisation solvent: mixture (V/V) of ethyl acetate and petroleumether

EXAMPLE 45 5-hydroxy-2-thiosemicarbazono-indan-1,3-dione

Raw materials: 5-hydroxyindan-1,2,3-trione, monohydrate,thiosemicarbazide hydrochloride, reflux for 2 hours.

Yield: 78%; M.P.>265° C.; IR: υ OH=3420 cm⁻¹, υ NH=3300 and 3120 cm⁻¹, υCO=1710 and 1680 cm⁻¹

Recrystallisation solvent: mixture (V/V) of ethyl acetate and petroleumether

EXAMPLE 46 5,6-dimethoxy-2-semicarbazono-indan-1,3-dione, monohydrate

Raw materials: 5,6-dimethoxyindan-1,2,3-trione, monohydrate,semicarbazide hydrochloride

Yield: 60%; M.P.>265° C.; IR: υ NH=3420 and 3300 cm⁻¹ ; υ CO=1730 and1680 cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 47 5,6-dimethoxy-2-(4-phenyl semicarbazono)-indan-1,3-dione,monohydrate

Raw materials: 5,6-dimethoxyindan-1,2,3-trione, monohydrate, 4-phenylsemicarbazide hydrochloride

Yield: 80%; M.P.>265° C.; IR: υ NH=3240 cm⁻¹ ; υ CO=1730, 1710 and 1670cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 48 2-[4-(3-trifluoromethylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3-trifluoromethyl phenyl)-semicarbazidehydrochloride

Yield: 70%; M.P. 230° C.; IR: υ NH=3360 and 3180 cm⁻¹ ; υ CO=1730 and1680 cm⁻¹

Recrystallisation solvent: ethyl acetate

EXAMPLE 49 2-[4-(2-trifluoromethylphenyl)-semicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(2-trifluoromethyl phenyl)-semicarbazidehydrochloride

Yield: 70%; M.P. 160° C.; IR: υ=3360 and 3180 cm⁻¹ ; υ CO=1740 and 1680cm⁻¹

Recrystallisation solvent: a mixture (V/V) of ether and isopropanol

EXAMPLE 50 2-[4-(3-bromophenyl)-thiosemicarbazono]indan-1,3-dione

Raw materials: ninhydrin, 4-(3-trifluoromethyl phenyl)-semicarbazidehydrochloride

Yield: 75%; M.P. 180° C.; IR: υ NH=3360 and 3180 cm⁻¹ ; υ CO=1730 and1680 cm⁻¹

Recrystallisation solvent: methanol

EXAMPLE 51 2-[4-(4-bromophenyl)-thiosemicarbazono]indan-1,3-dione

Raw materials:ninhydrin, 4-(4-bromophenyl)-thiosemicarbazidehydrochloride

Yield: 50%; M.P. 230° C.; IR: υ NH=3340 cm⁻¹ ; υ CO=1730 and 1700 cm⁻¹

EXAMPLE 52 2-[4-(pyridin-4-yl) semicarbazono]indan-1,3-dione

70 mmols of 4-pyridyl semicarbazide in suspension in 100 ml ethanol wereadded at ambient temperature to 70 mmols of2,2-dihydroxy-1,3-dioxo-2H-indene in solution in 100 ml ethanol. Thereaction mixture, which became yellow, was kept agitated at ambienttemperature for 24 hours. The resulting precipitate was filtered overfritted glass and washed in ether and in pentane. The crystals, whichwere yellow, were purified on a silica column, average pressure, andrecrystallised. They were dried overnight in vacuo at 50° C.

Yield: 74%; M.P.>260° C.; IR (KBr): υ NH=3300 cm⁻¹ ; υ CO=1730 and 1670cm⁻¹

NMR of ¹ H (200 MHz, DMSOd₆): δ (ppm) 10.65 (1s, 1H, NH); 8.45 (d, 2H,H-2', H6', J2'-3' and 5'-6'=6 Hz); 8.00 (s, 4H, H-4, H-5, H-6, H-7);7.65 (d, 2H, H-3', H-5', J2'-3' and 5'-6'=6 Hz)

Recrystallisation solvent: ethyl acetate

EXAMPLE 53 2-[4-(2,4-diflourophenyl)semicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene; 4-(2,4-difluorophenyl)semicarbazide, hydrochloride

Yield: 80%; M.P. 231° C.; IR (KBr): υ NH=3300 and 3220 cm⁻¹ ; υ C=O=1725and 1700 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 13.53 (1s, 1H, NH); 12.21 (1s,1H, NH); 7.98 (s, 4H, H-4, H-5, H-6, H-7); 7.93 (m, 1H, H-3'); 7.30 (m,1H, H-5'); 7.10 (s, 1H, H-6')

Recrystallisation solvent: ethyl acetate

EXAMPLE 54 2-[4-(2,6-difluorophenyl)semicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene;4-(2,6-difluorophenyl)semicarbazide, hydrochloride

Yield: 74%; M.P. 268° C.; IR (KBr): υ NH=3300 and 3220 cm⁻¹ ; υ CO=1725and 1700 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.47 (1s, 1H, NH); 9.98 (1s, 1H,NH); 8.00 (s, 4H, H-4, H-5, H-6, H-7); 7.49 (m 1H, H-4'); 7.27 (t 2H,H-3', H-5', JH5'-4'=JH3'-4'=7.91 Hz)

Recrystallisation solvent: ethyl alcohol

EXAMPLE 55 2-[4-(4-trifluoromethylphenyl)semicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene;4-(4-trifluoromethylphenyl)semicarbazide, hydrochloride

Yield: 90%; M.P. 254° C. (decomposition); IR (KBr): υ NH=3280 and 3220cm⁻¹ ; υ CO=1740 and 1700 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.56 (1s, 1H, NH ); 10.73 (1s,1H, NH ); 8.00 (s, 4H, H-4, H-5, H-6, H-7); 7.80 (d, 2H, H-3', H-5',JH3'-2' and 6'-5'=8.4 Hz) 7.72 (d, 2H, H-2', H-6', JH3'-2' and 6'-5'=8.4Hz)

Recrystallisation solvent: dichloromethane

EXAMPLE 562-[4-(2,4-difluoro-6-ethoxyphenyl)semicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene;4-(2,4-difluoro-6-ethoxyphenyl)semicarbazide, hydrochloride

Yield: 79%; M.P. 203° C.; IR (KBr): υ NH=3240 cm⁻¹ ; υ CO=1730, 1710 and1670 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆); δ (ppm) 13.13 (s, 1H, NH); 9.28 (s, 1H,NH); 7.94 (s, 4H, H-4, H-5, H-6, H-7); 7.31 (m, 1H, H-3'); 7.19 (m, 1H,H-5'); 4.20 (q, 2H, CH₂, J=8 Hz); 1.32 (t, 3H, CH₃, J=8 Hz)

Recrystallisation solvent: dichloromethane

EXAMPLE 57 2-[4-(4-fluorophenyl)thiosemicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene;4-(4-fluorophenyl)thiosemicarbazide, hydrochloride

Yield: 60%; M.P. 209° C.; IR (KBr): υ NH=3270 and 3210 cm⁻¹ ; υ CO=1725and 1680 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.85 (1s, 1H, NH); 11.24 (1s,1H, NH); 8.00 (s, 4H, H-4, H-5, H-6, H-7); 7.60 (m, 2H, H-3', H-5');7.24 (t, 2H, H-2', H-6', JH2'-3' and 5'-6'=8.9 Hz)

Recrystallisation solvent: dichloromethane

EXAMPLE 58 2-[4-(2-fluorophenyl)thiosemicarbazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene;(2-fluorophenyl)thiosemicarbazide, hydrochloride

Yield: 77%; M.P. 224° C.; IR (KBr): υ NH=3240 and 3200 cm⁻¹ ; υ CO=1720and 1680 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.89 (1s, 1H, NH): 11.00 (1s,1H, NH); 8.00 (s, 4H, H-4, H-5, H-6, H-7); 7.49 (m, 1H, H-3'); 7.34 (m,3H, H-4', H-5', H-6').

Recrystallisation solvent: ethyl ether

E. Preparation of formula (If) compounds

METHOD 5

40 ml of an aqueous solution containing 5.6 mmols of hydrazinocarbonylhydrazine of hydrazinothiocarbonyl hydrazine was added to a solution of5.6 mmols of 2,2-dihydroxy-1,3-dioxo-2H-indene in 30 ml ethanol.

The reaction mixture was agitated at ambient temperature for 7 hours andthe resulting white precipitate was dried on suction pump, washed inethanol and dried. The precipitate was then suspended in 20 ml ethanol,followed by addition of two drops of concentrated hydrochloric acid. Themixture was refluxed for 30 minutes and the resulting yellow-orangeproduct was precipitated, dried and recrystallised.

EXAMPLE 59 2-(phenylhydrazinocarbonylhydrazono)indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene; phenylhydrazinocarbonyl hydrazine

Yield: 98%; M.P. 245° C.; IR (KBr): υ NH=3320 cm⁻¹ ; υ CO=1740, 1720 and1680 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 13.25 (s, 1H, NH); 9.37 (s, 1H,NH); 8.17 (s, 1H, NH); 7.95 (s, 4H, H-4, H-5, H-6, H-7); 7.23 (m, 2H,H-2', H-6'); 7.30 (m, 3H, H-3', H-4', H-5')

Recrystallisation solvent: acetone

EXAMPLE 60 2-[(4-fluorophenyl)hydrazinocarbonylhydrazino]indan-1,4-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene.(4-fluorophenyl)hydrazinocarbonyl hydrazine

Yield: 67%; M.P. 250° C.; IR (KBr): υ NH=3240 and 3320 cm⁻¹ ; υ CO=1740and 1700 cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 13.25 (1s, 1H, NH); 9.43 (1s, 1H,NH); 8.20 (1s, 1H, NH); 7.95 (s, 4H, H-4, H-5, H-6, H-7); 7.10 (m, 2H,H-3', H-5'); 6.88 (m, 2H, H-2', H-6')

Recrystallisation solvent: ethanol/acetone 50/50%

F. Preparation of formula (Ig) compounds

METHOD 6

10 ml of an aqueous solution containing 30 mmols of (arylimino)methylthiohydrazine were added to a solution of 30 mmols of2,2-dihydroxy-1,3-dioxo-2H-indene in 70 ml ethanol.

The reaction mixture was brought to 60° C. for 30 minutes and theresulting maroon-orange precipitate was dried on suction pump when hot,dried and recrystallised.

EXAMPLE 61

2-[(phenylimino)methylthiohydrazono]indan-1,3,-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene(phenylimino)methylthiohydrazine

Yield: 40%; M.P. 200° C.; IR (KBr): υ NH=3200 cm⁻¹ ; υ CO=1720 and 1690cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.75 (1s, 1/2H, NH); 9.63 (1s,1/2H, NH); 7.98 (d, 1H, H-2' or H-6', JH2'-3'=7.4 Hz); 7.92 (s, 4H, H-4,H-5, H-6, H-7); 7.44 (m, 2H, H-3', H-5'); 7.21 (t, 1H, H-4',JH4'-5'=7.4); 6.97 (d, 1H, H-2' or H-6', JH2'-3'=7.4 Hz); 2.50 (s, 3H,CH₃)

Recrystallisation solvent: Ethyl acetate

EXAMPLE 62 2-[(4-fluorophenylimino)methylthiohydrazono]indan-1,3-dione

Raw materials: 2,2-dihydroxy-1,3-dioxo-2H-indene(4-fluorophenylimino)methylthiohydrazine

Yield: 50%; M.P.>260° C.; IR (KBr): υ NH=3180 cm⁻¹ ; υ CO=1740 and 1680cm⁻¹

NMR of ¹ H (200 MHz, DMSO d₆): δ (ppm) 12.86 (s, 1/2H, NH ); 9.78 (s,1/2H, NH ); 8.14 (d, 1H, H-2' or H-6', JH2'-3'=7.4 Hz); 8.00 (s, 4H,H-4, H-5, H-6, H-7); 7.37 (m, 2H, H-3', H-5'); 7.13 (d, 1H, H-2' orH-6', JH2'-3'=7.4 Hz); 2.61 (s, 3H, CH₃)

Recrystallisation solvent: acetone

G. Preparation of formula (Ii)-(Ik) compounds

METHOD 7 EXAMPLE 63 1,2-(4-phenylsemicarbazono)-3-indanone

Raw materials: Ninhydrin, 4-phenyl semicarbazide hydrochloride

Yield: 70%; M.P.>260° C.; IR: υ NH=3360, 3325 and 3300 cm⁻¹ ; υ CO=1700and 1675 cm⁻¹

Precipitate washed in ethanol

EXAMPLE 64 1-oximino-2-(4-phenylsemicarbazono)-3-indanone

0.01 mol of hydroxylamine hydrochloride and 0.01 mol sodium acetate insolution in 20 ml water were added to a solution of 0.01 mol of2-(4-phenyl semicarbazono)-indan-1,3-dione in 150 ml ethanol. Thereaction mixture was refluxed for 1 hour, then the ethanol waseliminated at reduced pressure. The resulting crystals were dried onsuction pump, washed in water, dried and recrystallised fromisopropanol.

Yield: 70%; M.P. 240° C.; IR: υ OH=3400 cm⁻¹ ; υ NH=3300 and 3240 cm⁻¹,υ CO=1710 cm⁻¹

H. Preparation of formula (Il) and (Im) compounds

METHOD 9 EXAMPLE 65 1,3-dioximino-2-(4-phenylsemicarbazono)-indan

0.02 mol of hydroxylamine hydrochloride and 0.01 mol sodium acetate insolution in 20 ml water were added to a solution of 0.01 mol of2-(4-phenyl semicarbazono)indan-1,3-dione in 150 ml ethanol. Thereaction mixture was refluxed for 1 hour, then the ethanol waseliminated at reduced pressure. The resulting crystals were dried onsuction pump, washed in water, dried and recrystallised from ethylacetate.

Yield: 65%; M.P.>265° C.; IR: υ OH=3450 m⁻¹, υ NH=3180 cm⁻¹, υ CO=1680cm⁻¹

Note that the infrared spectra hereinafter were determined using KBrpellets.

The following are the NMR spectra of the compounds in the previousexamples. These spectra were determined on an NMR apparatus, 200 MHz, insolution in DMSO (D6). They are described in accordance with thefollowing protocol: shift (δ) in ppm, shape of signal, number ofprotons, nature of protons, coupling constants if applicable.

The aromatic protons on indan were numbered as follows: ##STR21##

In the case where R and R₁ comprise a heterocyclic ring or form a groupcontaining a heterocyclic ring, the protons in the ring are numberedfrom the heteroatom in the direction of the bond to the main substrate.

NMR spectra

EXAMPLE A 5-Hydroxyindane-1,3-dione

7.78 (d, 1H, H-7, J H6-7=8.3 Hz) 7.26 (d ,1H, H-6, J H6-7=8.3 Hz) 7.11(1s, 1H, H-4) 3.25 (s, 3H, CH2)

EXAMPLE B 2-Bromo-5-hydroxyindane-1,3-dione

11,55 (1s, OH) 7.90 (dd, 1H, H-6, J H6-4=2.93 Hz; J H6-7=8.3 Hz) 7.39(d, 1H, H-7, J H6-7=8.3 Hz) 7.21 (s, 1H, H-4) 5.50 (s, 1H, H2)

EXAMPLE C 5-Hydroxyindane-1,2,3-trione, monohydrate

11.50(1s, 1H, OH) 7.90 (d, 1H, H7, J H6-7=5.9 Hz) 7.40 (m, 2H, H4, H6)

EXAMPLE D 5,6-Dimethoxyindane-1,2,3-trione, monohydrate

7.40 (1s, 2H, H-4, H-7) 4.03 (s, 6H, 2CH3O)

EXAMPLE E 6-Hydroxy-5-methoxyindane-1,2,3-trione, monohydrate

11.21 (1s, 1H, OH) 7.28 (m, 2H, H-4, H-7) 4.03 (s, 6H, 2CH3O)

EXAMPLE F 2-oximino-5-hydroxyindane-1,3-dione

9.16 (1s, 1H, OH) 7.83 (dd, 1H, H6, JH6-7=9.0 Hz and JH4-6=3.0 Hz) 7.21(m, 2H, H7, H4)

EXAMPLE 1 2-Hydroxy-2-[4-2-hydroxyphenyl)-semicarbazido]indane-1,3-dione

9.55 (1s, 1H, NH) 8.27 (s, 1H, OH) 8.00 (s, 4H, H-4, H-5, H-6, H-7) 7.90(m, 2H, NH, H-3') 7.13 (1s, 1H, OH) 6.71 (m, 3H, H-4', H-5', H-6') 6.30(1s, 1H, NH)

EXAMPLE 2 2-semicarbazono-indane-1,3-dione

12.55 (s, 1H,NH) 7.95 (s, 4H, H-4, H-5, H-6, H-7) 7.41 (s, 2H, NH2)

EXAMPLE 3 2-(4-Phenylsemicarbazono)-indane-1,3-dione

12.55 (s, 1H, NH) 10.35 (s, 1H, NH) 8.00 (s, 4H, H-4, H-5, H-6, H-7)7.65 (d, 2H, H-2', H-6', J H2'-3' & 5'-6'=8.2 Hz) 7.35 (dd, 2H, H-3',H-5', J H2'-3' & 5'-6'=8.2 Hz) 7.10 (m, 1H, H-4')

EXAMPLE 4 2-[4-(2-hydroxyphenyl)-semicarbazono]indane-1,3-dione

12.55 (s, 1H, NH) 10.18 (s, 1H, OH) 9.64 (s, 1H, NH) 7.97 (s, 5H. H-4,H-5, H-6, H-7, H-6') 6.92 (m, 3H, H-3', H-4', H-5')

EXAMPLE 5 2-(4-Phenylthiosemicarbazono)indane-1,3-dione

12.50 (1s, 1H, NH) 10.35 (1s, 1H, NH) 7.95 (s, 4H, H-4, H-5, H-6, H-7)7.58 (d, 2H, H-2', H-6', J H2'-3' & 5'-6'=8.3 Hz) 7.34 (dd, 2H, H-3',H-5', J H2'-3' & 5'-6'=8.3 Hz) 7.07 (dd, 1H, H-4', J H4'-5' & 3'-4'=8.3Hz)

EXAMPLE 6 2-[4-(2-Methoxyphenyl)-semicarbazono]indane-1,3-dione

12.57 (s, 1H, NH) 9.69 (s, 1H, NH) 8.03 (m, 1H, H-6') 7.95 (s, 4H, H-4,H-5, H-6, H-7) 7.06 (m, 2H, H-3', H-5') 6.97 (m, 1H, H-4') 3.89 (s, 3H,CH3)

EXAMPLE 7 2-[4-(3-Methoxyphenyl)-semicarbazono]indane-1,3-dione

12.48 (1s, 1H, NH) 10.32 (1s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7)7.22 (m, 3H, H-4', H-5', H-6') 6.65 (d, 1H, H-3', J H3'-4'=7.8 Hz) 3.75(s, 3H, CH3O)

EXAMPLE 8 2-[4-(4-Methoxyphenyl)-semicarbazono]indane-1,3-dione,monohydrate

12.46 (1s, 1H, NH) 10.22 (1s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7)7.50 (d, 2H, H-2', H-6', J H2'-3' & 5'-6'=8.8 Hz) 6.92 (d, 2H, H-3',H-5', J H2'-3' & 5'-6'=8.8 Hz) 3.73 (s, 3H, CH3O)

EXAMPLE 9 2-[4-(2,5-Dimethoxyphenyl)-semicarbazono]indane-1,3-dione

12.54 (1s, 1H, NH) 9.68 (1s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7)7.73 (m, 1H, H-6') 6.98 (d, 1H, H-3', J H3'-4'=8.3 Hz) 6.63 (dd, 1H,H-4', J H3'-4'=8.3 Hz) 3.83 (s, 3H, CH3O) 3.70 (s, 3H, CH3O)

EXAMPLE 10 2-[4-(3,5-Dimethoxyphenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 9.75 (s, 1H, NH) 8.00 (s, 4H, H-4, H-5, H-6, H-7) 6.85(m, 2H, H-2', H-6') 6.63 (m, 1H, H-4') 3.75 (s, 6H, 2CH3O)

EXAMPLE 11 2-[4-(3,4-Dimethoxyphenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 10.19 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.20 (m, 2H, H-2', H-6') 6.92 (d, 1H, H-5', J H5'-6'=8.8 MHz) 3.75 (s,3H, CH3O) 3.73 (s, 3H, CH3O)

EXAMPLE 122-[4-(2-Chloro-5-methoxyphenyl)-semicarbazono]indane-1,3-dione

12.63 (s, 1H, NH) 9.86 (s, 1H, NH) 7.93 (s, 4H, H-4, H-5, H-6, H-7) 7.62(d, 1H, H-6', J H4'-6'=3.0 Hz) 7.40 (d, 1H, H-3', J H3'-4'=8.8 Hz) 6.76(dd, 1H, H-4', J H3'-4'=8.8 Hz & J H4'-6'=3.0 Hz) 3.76 (s, 3H, CH3O)

EXAMPLE 13 2-(4,4-Diphenylsemicarbazono)indane-1,3-dione

12.48 (s, 1H, NH) 7.93 (m. 5H, Ph) 7.89 (s, 4H, H-4, H-5, H-6, H-7) 7.85(m, 5H, Ph)

EXAMPLE 14 2-[4-(2-Methylphenyl)-semicarbazono]indane-1,3-dione

12.57 (s, 1H, NH) 9.63 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7) 7.60(d, 1H, H-6', J H 5'-6'=7.7 Hz) 7.23 (m, 2H, H-3', H-5') 7.14 (m, 1H,H-4') 2.27 (s, 3H, CH3)

EXAMPLE 15 2-[4-(3-Methylphenyl)-semicarbazono]indane-1,3-dione

12.51 (s, 1H, NH) 10.29 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.38 (m, 2H, H-2', H-6') 7.24 (t, 1H, H-5', J H4'-5' & J H5'-6'=7.3 Hz)6.90 (d, 1H, H-4',J H4'-5'=7.3 Hz) 2.30 (s, 3H, CH3)

EXAMPLE 16 2-[4-(4-Methylphenyl)-semicarbazono]indane-1,3-dione

12.47 (s, 1H, NH) 10.26 (s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7)7.48(d, 2H, H-2', H-6', J H2'-3' & J H5'-6'=8.3 Hz) 7.14(d, 2H, H-3',H-5', J H2'-3' & J H5'-6'=8.3 Hz) 2.26 (s, 3H, CH3)

EXAMPLE 17 2-[4-(4-Propylphenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 10.29 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.48 (d, 2H, H-2', H-6', J H2'-3' & J H5'-6'=8.3 Hz) 7.16 (d, 2H, H-3',H-5', J H2'-3' & J H5'-6'=8.3 Hz) 2.50 (m, 2H, CH2) 1.57 (m, 2H, CH2)0.89 (t, 3H, CH3, J CH3-CH2=6.8 Hz)

EXAMPLE 18 2-[4-(4-Tert-butylphenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 10.29 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.49 (d, 2H, H-2', H-6', J H2'-3' & J H5'-6'=8.3 Hz) 7.36 (d, 2H, H-3',H-5', J H2'-3' & J H5'-6'=8.3 Hz) 1.27 (s, 9H, t-Bu)

EXAMPLE 19 2-[4-(2-Chlorophenyl)-semicarbazono]indane-1,3-dione

12.61 (s, 1H, NH) 9.91 (s, 1H, NH) 7.98 a 7.91 (1s, 5H, H-4, H-5, H-6,H-7, H-6') 7.53 (d, 1H, H-3', J H3'-4'=7.3 Hz) 7.38 (t, 1H, H-5', JH5'-4' & J H5'-6'=7.3 Hz) 7.20 (t, 1H, H-4', J H3'-5' & J H4'-5'=7.3 Hz)

EXAMPLE 20 2-[4-(2-Chloro-6-methylphenyl)-semicarbazono]indane-1,3-dione

12.45 (s, 1H, NH) 9.82 (s, 1H, NH) 7.98 (s, 4H, H-4, H-5, H-6, H-7)7.37-7.24 (m, 3H, H-3', H-4', H-5') 2.49 (s, 3H, CH3)

EXAMPLE 21 2-[4-(4-Chlorophenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 10.47 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.60 (d, 2H, H-2', H-6', J H2'-3' & J H5'-6'=8.8 Hz) 7.40 (d, 2H, H-3',H-5', J H2'-3' & J H5'-6'=8.8 Hz)

EXAMPLE 22 2-[4-(2,5-Diethoxyphenyl)-semicarbazono]indane-1,3-dione

12.50 (s, 1H, NH) 9.52 (s, 1H, NH) 7.99 (s, 4H, H-4, H-5, H-6, H-7) 7.71(d, 1H, H-6', J H4'-6'=2.9 Hz) 7.00 (d, 1H, H-3', J H3'-4'=8.8 Hz) 6.63(dd, 1H, H-4', J H3'-4'=8.8 Hz & J H4'-6'=2.9 Hz) 4.06 (q, 2H, CH2) 3.90(q, 2H, CH2) 1.38 (m, 6H, 2CH3)

EXAMPLE 23 2-(4-Ethylthiosemicarbazono)-indane-1,3-dione

12.57 (s, 1H, NH) 9.68 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7) 3.63(q, 2H, CH2, J CH3-CH2=6.35) 1.17 (d, 3H, CH3, J CH3-CH2=6.35)

EXAMPLE 24 2-(4-Methylthiosemicarbazono)-indane-1,3-dione

12.62 (s, 1H, NH) 10,00 (s, 1H, NH) 7.98 (s, 4H, H-4, H-5, H-6, H-7)3.07 (s, 3H, CH3)

EXAMPLE 25 2-[4-(4-Ethylphenyl)-semicarbazono]-indane-1,3-dione

12.50 (s, 1H, NH) 10.27 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.48 (d, 2H, H-2', H-6') 7.17 (d, 2H, H-3', H-5') 3.33 (q, 2H, CH2) 1.17(m, 3H, CH3)

EXAMPLE 26 2-[4-(3-Ethoxyphenyl)-semicarbazono]-indane-1,3-dione

12.57 (s, 1H, NH) 10,30 (s, 1H, NH) 7.95 (s, 4H, H-4, H-5, H-6, H-7)7.30 (m, 3H, H-2', H-5', H-6') 7.05 (d, 1H, H-4', J H4'-5'=7.8 Hz) 3.93(q, 2H, CH2, J CH3-CH2=6.35) 1.35 (t, 3H. CH3, J CH3-CH2=6.35)

EXAMPLE 27 2-[4-(4-Ethoxyphenyl)-semicarbazono]-indane-1,3-dione

12.47 (1s, 1H, NH) 10,17 (1s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7)7.45 (d, 2H, H-2', H-6', J H2'-3'=8.8 Hz & H5'-6'=8.8 Hz) 6.90 (d, 2H,H-3', H-5', J H2'-3'=8.8 Hz & H5'-6'=8.8 Hz) 3.98 (q, 2H, CH2, JCH3-CH2=6.8) 1.34 (t, 3H, CH3, J CH3-CH2=6.8)

EXAMPLE 28 2-[4-(2,4-Dichlorophenyl)-semicarbazono]-indane-1,3-dione

12.66 (s, 1H, NH) 10,01 (s, 1H, NH) 8.04 (s, 4H, H-4, H-5, H-6, H-7)7.97 (d, 1H, H-6') 7.85 (s, 1H, H-3') 7.47 (d, 1H, H-5')

EXAMPLE 292-[4-(3,4-Methylenedioxyphenl)-semicarbazono]-indane-1,3-dione

12.44 (s, 1H, NH) 10,23 (s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7)7.23 (s, 1H, H-2') 6.90 (m, 2H, H-5', H-6') 5.99 (s, 2H, CH2)

EXAMPLE 30 2-[4-(2-Fluorophenyl)-semicarbazono]-indane-1,3-dione

12.70 (s, 1H, NH) 10,30 (s, 1H, NH) 8.04 (m, 1H, H-3') 7.97 (s, 4H, H-4,H-5, H-6, H-7) 7.20 (m, 3H, PHe)

EXAMPLE 31 2-[4-(3-Fluorophenyl)-semicarbazono]-indane-1,3-dione

12.50 (s, 1H, NH) 10,56 (s, 1H, NH) 7.98 (s, 4H, H-4, H-5, H-6, H-7)7.57 (d, 1H, H-6', J H5'-6'=10.25 Hz) 7.41 (m, 2H, H-2', H-4') 7.30 (m,1H, H-5')

EXAMPLE 32 2-[4-(4-Fluorophenyl)-semicarbazono]-indane-1,3-dione

12.30 (s, 1H, NH) 10,41 (s, 1H, NH) 7.98 (s, 4H, H-4, H-5, H-6, H-7)7.60 (m, 2H, H-3', H-5') 7.20 (m, 2H, H-2', H-6')

EXAMPLE 33 2-[4-(2-Bromophenyl)-semicarbazono]-indane-1,3-dione

12.47 (s, 1H, NH) 9.70 (s, 1H, NH) 7.98 (s, 4H, H-4, H-5, H-6, H-7) 7.84(d, 1H, H-3', J H3'-4'=8.3 Hz) 7.68 (d, 1H, H-6', J H5'-6'=8.3 Hz) 7.43(t, 1H, H-5', J H5'-6' & 4'-6'=8.3 Hz) 7.16 (t, 1H, H-4', J H3'-4' &:H54'-5'=8.3 Hz)

EXAMPLE 34 2-[4-(4-Bromophenyl)-semicarbazono]-indane-1,3-dione 12.44(s, 1H, NH) 10.36 (s, 1H, NH) 7.96 (s, 4H, H-4, H-5, H-6, H-7) 7.53 (s,4H, H-2',H-3',H-5', H-6') EXAMPLE 352-[4-(2-Hydroxyethyl)-semicarbazono]-indane-1,3-dione

12.11 (s, 1H, NH) 10.20 (s, 1H, NH) 7.96 (s, 5H, H-4, H-5, H-6, H-7, NH)4.78 (t, 1H, OH) 3.47 (m, 2H, CH2-N) 3.27 (m, 2H, CH2-O)

EXAMPLE 36 2-[4-(2-Acetoxyphenyl)-semicarbazono]-indane-1,3-dione

12.51 (s, 1H, NH) 9.78 (s, 1H, NH) 7.97 (s, 4H, H-4, H-5, H-6, H-7) 7.80(m, 1H, H-3') 7.28 (m, 3H, H-4', H-5', H-6') 2.38 (s, 3H, CH3)

EXAMPLE 37 5-methoxy-2-(4-phenylsemicarbazono)-indane-1,3-dione

12.45 (s, 1H, NH) 10.26 (s, 1H, NH) 7.90 (d, 1H, H-7, J H6-7=7.8 Hz)7.58 (d, 1H. H-6, J H6-7=7.8 Hz) 7.38 (m,-5H, H-2', H-3', H-5', H-6',H4) 7.07 (m, 1H, H-4') 3.99 (s, 3H, OCH3)

EXAMPLE 38 5-Methoxy-2-(4-phenylthiosemicarbazono)-indane-1,3-dione

12.85 (1s, 1H, NH) 11.17 (s, 1H, NH) 7.96 (d, 1H, H-7, J H6-7=7.8 Hz))7.59(d, 1H, H-6, J H6-7=7.8 Hz)) 7.45(m, 4H, Ph) 7.27 (m, 1H, Ph) 3.99(s, 3H, OCH3)

EXAMPLE 39 5-methoxy-2-semicarbazono-indane-1,3-dione

11.94 (s, 1H, NH) 7.90 (d, 1H, H-7, J H6-7=8.3 Hz) 7.87 (m, 4H, H-4,H-6, NH2) 3.98 (s, 3H, CH3O)

EXAMPLE 405-methoxy-2-[4-(2-Hydroxyphenyl)-semicarbazono]-indane-1,3-dione

12.50 (s, 1H, OH) 10.11 (s, 1H, NH) 9.53 (s, 1H, NH) 7.95 (m, 2H, H-7,H-3') 7.45 (m, 2H, H-4, H-6) 6.85 (m, 3H, H-4', H-5', H-6') 3.99 (s, 3H,CH3O)

EXAMPLE 41 5-methoxy-2-thiosemicarbazono-indane-1,3-dione

12.50 (1s, 1H, NH) 12.41 (s, 1H, SH 9.38 (s, 1H, NH) 7.95 (d, 1H, H-7, JH6-7=7.8 Hz) 7.47 (m, 2H, H-4, H-6) 3.98 (s, 3H, CH3O)

EXAMPLE 42 5-Hydroxy-2-(4-phenylsemicarbazono)-indane-1,3-dione

12.30 (1s, 1H, NH) 11.70 (1s, 1H, NH) 10.29 (1s, 1H, OH) 7.87 (d, 1H,H-6, JH5-6=8.3 Hz) 7.60 (d, 1H, H-5, JH5-6=8.3 Hz) 7.35 (m, 3H, H-4,H-2', H-6') 7.28 (m, 2H, H-3', H-5') 7.18 (m, 1H, H-4')

EXAMPLE 43 5-Hydroxy-2-semicarbazono-indane-1,3-dione

11.90 (1s, 1H, NH) 7.84 (d, 1H, H-7, J H6-7=8.3 Hz) 7.30 (m, 4H, H-4,H-6, NH2)

EXAMPLE 44 5-Hydroxy-2-(4-phenylthiosemicarbazono)-indane-1,3-dione

11.96 (s, 1H, NH) 11.12 (s, 1H, NH) 7.84 a 7.20 (m, 8H, Ph)

EXAMPLE 45 5-Hydroxy-2-thiosemicarbazono-indane-1,3-dione

12.55 (1s, 1H, NH) 12.42 (s, 1H, OH) 9.36 (s, 1H, SH) 8.78 (s, 1H, NH)7.89 (d, 1H, H-7, J H6-7=8.3 Hz) 7.27 (m, 2H, H-4, H-6)

EXAMPLE 46 5,6-Dimethoxy-2-semicarbazono-indane-1,3-dione

11.78 (s, 1H, NH) 7.39 (s, 1H, H-4) 7.35 (s, 1H, H-7) 7.26.(s, 2H, NH2)3.98 (s, 6H, 2CH3)

EXAMPLE 47 5,6-Dimethoxy-2-(4-phenylsemicarbazono)-indane-1,3-dione

12.30 (s, 1H, NH) 10.18 (s, 1H, NH) 7.59 (m, 7H, H-4, H-7, Ph) 3.99 (s,6H, 2CH3)

EXAMPLE 482-[4-(3-Trifluoromethylphenyl)-semicarbazono]-indane-1,3-dione

12.50 (1s,1H, NH) 10.68 (s, 1H, NH) 8.05 (s, 1H, H2') 7.99 (s, 4H, H-4,H-5, H-6, H-7) 7.83 (d, 1H, H-4', J H4'-5'=7.8 Hz) 7.60 (t, 1H, H-5', JH4'-5'=& JH5'-6'=7.8 Hz) 7.44 (d, 1H, H-6', J H5'-6'=7.8 Hz)

EXAMPLE 492-[4-(2-Trifluoromethylphenyl)-semicarbazono]-indane-1,3-dione

12.57 (1s, 1H, NH) 9.85 (s, 1H, NH) 7.09 (s. 4H, H-4, H-5, H-6, H-7)7.80 (m, 3H, H-3', H-5', H-6') 7.74 (m, 1H, H-3')

EXAMPLE 50 2-[4-(3-Bromophenyl)-semicarbazono]-indane-1,3-dione

12.44 (s, 1H, NH) 10.48 (s, 1H, NH) 7.93 (s, 4H, H-4, H-5, H-6, H-7)7.87 (s, 1H, H-2') 7.45 (d, 1H, H-4', JH4'-5'=6.3 Hz) 7.25 (m, 2H, H-5',H-6')

EXAMPLE 51 2-[4-(4-Bromophenyl)-thiosemicarbazono]-indane-1,3-dione

12.88 (s, 1H, NH) 10.48 (s, 1H, NH) 8.02 (s, 4H, H-4, H-5, H-6, H-7)7.60 (s, 4H, H-2', H-3', H-5', H-6')

EXAMPLE 63 1,2-(4-Phenylsemicarbazono)-3-indanone

11.80 (s, 2H, NH) 9.80 (s, 2H, NH) 7.97 (m, 2H, H-4, H-7) 7.65 (m, 6H,H-5, H-6, 2H-2', 2H-6') 7.56 (m, 4H, 2H-3', 2H-5') 7.16 (m, 2H, 2H-4')

EXAMPLE 64 1-Oximino-2-(4-phenylsemicarbazono)-3-indanone

13.20 (s, 1H, NH) 11.65 (s, 1H, OH) 9.75 (s, 1H, NH) 8.56 (d, 1H, H-7, JH6-H7=7.14 Hz) 7.80 (m, 3H, H-4, H-5, H-6) 7.40 (m, 2H, h-3', H-5') 7.17(m, 1H, H-4')

EXAMPLE 65 1,3-Dioximino-2-(4-phenylthiosemicarbazono)-3-indanone

13.06 (1s, 1H, NH) 12.59 (1s, 1H, OH) 11.63 (1s, 1H, OH) 9.19 (1s, 1H,NH) 8.56 (d, 1H, H-7, H-4, J H6-7 & J H4-5=7.3 Hz) 7.64 (m, 4H, H-5,H-6, H-2', H-6') 7.33 (t, 2H, H-3', H-5', J H2'-3' & JH5'-6'=7.3 Hz)7.03 (t, 1H, H-4', J H3'-4' & JH4'-5'=7.3 Hz)

A study of the compounds according to the invention has shown that theyhave various pharmacological properties. For example they are venotonicand in most cases do not affect the arterial system. They also increasethe capillary resistance, reduce vascular hyperpermeability induced bycertain inflammatory agents and have antilipoperoxidising, antiradicaland anti-inflammatory properties and activity in septic shock.

These properties are shown in mammals such as rats, guinea-pigs andrabbits, under in vitro (isolated vessels or vascular networks) and invivo conditions.

In the in vitro test, the compounds were solubilised in aqueoussolution, either pure or containing DMSO or alcohol.

In the in vivo test, the products were administered intravenously in theform of a pure aqueous solution or intraperitoneally in the form of anaqueous solution optionally containing DMSO or orally in solution or insuspension in carboxymethyl cellulose or in a composite aqueous solutioncontaining Tween® and DMSO in certain cases.

Pharmacological Study Models

The contractile effect was measured in vitro:

by the contractile force exerted by vascular rings, either quiescent orstimulated (electrically or by physiological agents) and maintainedunder isometric conditions, and

by the pressure exerted by vascular networks perfused at a constant flowrate.

In vivo, the arterial and venous pressure was measured under normalconditions and after cardiac arrest. During cardiac arrest, the venoustone was calculated from the venous and arterial pressure measured atequilibrium and corrected in dependence on the relative differences incompliance between these two networks (Samar and Coleman, Am. J.Physiol., 1978, 234:H94-100; Yamamoto et al., Am. J. Physiol., 1980,238:H823-828).

The increase in capillary resistance was estimated by modification ofthe petechial index (negative pressure inducing extravasation oferythrocytes) measured by a method derived from the Parrotangiosterrometer.

The vascular permeability was studied in vivo and in vitro by measuringthe extravasation of albumin or dye binding the albumin (Evans Blue). Invivo, hyperpermeability was induced by injection of a solution ofhistamine, bradykinin or zymosan. The in vitro models were used toobtain hyperpressure (over an isolated vascular region) and/orinflammatory vascular reactions.

The anti-inflammatory activity was demonstrated by measuring theinhibition of oedema and leucocyte migration after induction of pleurisyin the rat by injection of carrageenin into the pleural cavity (Almeidaet al., J. Pharmacol. Exp. Therap., 1980, 214:74).

The overall "free radical trapping" effect was studied in vitro in amodel using 1,1-diphenyl-2-picrylhydrazyl (DPPH) as stable free radical,the method being derived from that described by Lamaison et al., PlantesMedic. et phytotheraphie, XXII, 1988, 231-234.

The anti-oxidising activity was studied in vitro using a lipidperoxidation model based on peroxidation of an emulsion of linoleic acidby iron, the method being a modification of that described by Sutherlandet al., Arch. Biochem. Biophys. 1982, 214, 1-11.

The activity in septic shock was studied in the rat after induction by alipopolysaccharide endotoxin (15 mg/kg), the method being similar tothat described by Terashita et al., Eur. J. Pharmacol., 109, 257-261,1985.

Examples of Pharmacological Effects

The compounds according to the invention increase the contraction ofanimal saphena veins produced by noradrenalin and depolarisation(hyperpotassic solution) without in most cases affecting the arterialcontractile responses. For example, the compounds in Examples 3, 5 and32 (10 nM to 30 μM) produce a more than 50% increase (ED₅₀ ±0.3 microM)in contractions of the saphena veins of rabbits produced by KCl (40 mM).

The compound in Example 32, at its maximum concentration, increases by30 to 200% the contraction of the saphena veins in the rabbit inresponse to 0.3 micromolar noradrenalin.

The compounds in Examples 3 and 32 produce a more than 20% increase inthe basic venous tone of the rat without affecting the arterial pressureat doses of 1 to 3 picomols administered intravenously.

By way of illustration, the compound in Example 4 increases the basiccapillary resistance by 10 to 100%, when measured one to two hours afteradministration of 5-20 mg/kg intraperitoneally and up to 4 to 6 hoursafter oral administration of 5-20 mg/kg to the rat.

The compound in Example 8 reduces vascular permeability by 10 to 50%when measured one to two hours after intraperitoneal administration of5-20 mg/kg and 2 to 4 hours after oral administration of 5-20 mg/kg tothe rat.

The compound in Example 3, administered intraperitoneally twice in dosesof 20 mg/kg, inhibits oedema and leucocyte migration in the pleuralcavity, six hours after injection of carrageenin in the model ofpleurisy in the rat.

The compound in Example 1 has a maximum anti-radical effect of more than95% in the model using DPPH.

The compound in Example 3, at intravenous doses as low as 1microgram/kg, produces a more than 30% reduction in the initial drop inarterial pressure produced by the endotoxin and restores the arterialpressure after 30 minutes, where it remains reduced by 30% in thecontrol rats.

Toxicity

The compounds according to the invention have very low toxicity. Forexample after a single oral administration to the mouse, no deaths wereobserved at a dose of 1 g/kg of the compounds in Examples 3 and 32. Theonly observed effects, in certain cases, were coloured diarrhoea andcoloured urine, the latter being evidence of resorption of the product.

As the preceding shows, the compounds according to the invention can beused in human and animal therapy. They are particularly indicated, withregard to their vascular and anti-inflammatory components, infunctional, organic venous insufficiency and morbid haemorrhoid statesand in typically inflammatory complaints (osteo-articular,dermatological or cardio-vascular) and in states of shock consisting ofa considerable drop in arterial pressure, more particularly in states ofseptic (endotoxic) shock.

Functional venous insufficiency is characterised by dilation andhyperdistensibility of the surface veins of the lower limbs accompaniedby functional symptoms, i.e. pain in the lower limbs, oedema, andparaesthesia, e.g. tingling and fidgety legs. This morbid state maydevelop into organic venous insufficiency (varicose veins, deep valvularincontinence, etc) or into phlebo-thrombosis or ulcerous lesions.

In these venous states, an inflammatory component appears in the firststages and is shown more clearly in the advanced stages.

The invention therefore comprises use of the aforementioned compounds asactive substances in the preparation of drugs and pharmaceuticalcompositions for human or veterinary use and comprising at least one ofthe aforementioned compounds in association with a physiologicallyacceptable excipient or diluent.

The form of the drugs and pharmaceutical compositions will of coursedepend on the desired method of administration, inter alia oral,parenteral or rectal, and they can be formulated by conventional methodswith usual excipients and vehicles.

For example in the case of oral administration, they can be in the formof pills, tablets, capsules, solutions, syrups or suspensions.

The pills, tablets and capsules contain the active substance togetherwith a diluent (e.g. lactose, dextrose, sucrose, mannitol, sorbitol orcellulose), a lubricant (e.g. silica, talc or stearate, e.g. magnesiumstearate), a binder (e.g. starch, methyl cellulose or gum arabic) and adisintegrating agent (e.g. alginate) and are manufactured by knownmethods such as mixing, granulation, pelleting or coating.

The excipient in syrups can be glycerol, mannitol and/or sorbitol. Thesolutions and suspensions can contain water and an excipient such as anatural gum or gelose or sodium alginate or polyvinyl alcohol.

For parenteral administration, the drugs or composition can be in theform of solutions, emulsions or suspensions containing the activesubstance and a suitable excipient such as sterile water or sterileaqueous isotonic saline solutions.

For rectal administration, they can be in the form of suppositoriescontaining the active substance and a suitable excipient such as cocoabutter or polyethylene glycol.

The therapeutic dose of the active substances can be up to 1000 mg perday, depending on the method of administration, the age, weight andstate of the patient, and the therapeutic power of the active substance.

We claim:
 1. Indan compounds of the formula: ##STR22## wherein R₂ and R₃each independently represent H, C₁ -C₄ alkoxy or OH, and:a) each of Aand B is an oxygen atom and R and R₁ together form a group of theformula:1) ═NNHCONHR₅ where R₅ represents H, pyridyl, phenyl or phenylsubstituted by one, two or three groups selected from OH, CF₃, C₁ -C₄alkyl, C₁ -C₄ alkoxy, halogen, or hydroxyethyl; 2) ═NNHCON (phenyl)₂,;or 3) ═NNHCONHNHR₅ where R₅ is the same as defined above; or b) A is aN--OH group and B is an oxygen atom and R and R₁ together form a═NNHCONHR₅ group or a ═NNHCON (phenyl)₂ group, where R₅ is the same asdefined above; or c) A is a NNHCONHR₅ group and B is an oxygen atom andR and R₁ together form a ═NNHCONHR₅ group, where R₅ is the same asdefined above; or d) each of A and B is a N--OH group and R and R₁together form a ═NNHCONHR₅ group or a ═NNHCON (phenyl)₂ group, where R₅is the same as defined aboveand acid addition salts of salt-formingcompounds of formula (I).
 2. The indan compounds of claim 1, whereineach of A and B is an oxygen atom.
 3. The indan compounds of claim 1,wherein A is a N--OH group and B is an oxygen atom.
 4. The indancompounds of claim 1, wherein A is a NNHCONHR₅ group and B is an oxygenatom.
 5. The indan compounds of claim 1, wherein A and B are each aN--OH group and R and R₁ together form a ═NNHCONHR₅ group.
 6. The indancompounds of claim 1, wherein each of A and B is an oxygen atom and Rand R₁ together form a ═NNHCONHR₅ group.
 7. The indan compounds of claim1, wherein each of A and B is an oxygen atom and R and R₁ together forma ═NNHCON(phenyl)₂ group.
 8. The indan compounds of claim 1, whereineach of A and B is an oxygen atom and R and R₁ together form a═NNHCONHNHR₅ group.
 9. The indan compounds of claim 1, wherein A is aN--OH group and B is an oxygen atom and R and R₁ together form a═NNHCONHR₅ group.
 10. The indan compounds of claim 1, wherein A is aN--OH group and B is an oxygen atom and R and R₁ together form a═NNHCON(phenyl)₂ group.
 11. The indan compounds of claim 1, wherein eachof A and B is a N--OH group and R and R₁ together form a ═NNHCONHR₅group.
 12. The indan compounds of claim 1, wherein each of A and B is aN--OH group and R and R₁ together form a ═NNHCON(phenyl)₂ group. 13.2-(4-phenyl semicarbazono)-indan-1,3-dione.
 14. A pharmaceuticalcomposition comprising at least one compound or pharmaceuticallyacceptable salt thereof of claim 1 and a physiologically acceptableexcipient or diluent.
 15. A method for the treatment of functionalorganic venous insufficiency states, morbid hemorrhoid states,inflammatory complaints, states of shock consisting of a considerabledrop in arterial pressure and states of septic shock, in human oranimal, which comprises administering to a human or animal in need ofsuch a treatment an effective amount of a compound or salt thereof ofclaim 1.